Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies

Abstract

Background: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes.

Methods: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (¹⁸F-6-fluoro-L-dopa; ¹⁸F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, ¹⁸F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age.

Findings: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and ¹⁸F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and ¹⁸F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater ¹⁸F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with ¹⁸F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease.

Interpretation: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa.

Funding: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

Figure 1

FDOPA uptake, MP binding grouped by age ¹⁸F-FDOPA (F-DOPA) uptake (left panels) and ¹¹C-d-threo-methylphenidate (MP) binding (right panels) in the putamen of healthy controls, LRRK2 mutation carriers with or without manifest PD, and sporadic PD. A, B: Group comparisons of putamen FDOPA uptake and MP binding. *LRRK2-unaffected significantly less than healthy controls; p<0·0001. # LRRK2-unaffected significantly greater than LRRK2-PD/sPD; p<0·0001. LRRK2-PD and sPD groups are significantly different from healthy controls for all ages and regions. C, D: Putamen FDOPA uptake and MP binding as a function of disease duration in symptomatic LRRK2 mutation carriers. Each point represents a single patient; point shape indicates the specific LRRK2 mutation carried by the patient. Solid red line is the equivalent function in patients with sporadic Parkinson’s disease, with 95% confidence limits displayed as light red lines. The solid black line shows the effect of age in healthy controls starting at age 57 (equivalent to duration = 0).

Figure 2

Regional DASB Binding A: Group mean DASB binding potential in different volumes of interest (by reference tissue model); *age-adjusted ANCOVA significantly different; hypothalamus, p<0.0001; striatum, p=0·017; brainstem, p=0·014, corrected for multiple comparisons; whiskers indicate standard deviation. B: Absolute difference between group mean (bars) and healthy control mean (blue line) in each region C: Relative difference between healthy control mean (blue line) and binding potential for each participant (as a proportion of the mean healthy control value) in that region